ABSTRACT Dendritic cells (DCs) are central orchestrators of adaptive immunity, integrating innate immune sensing with antigen‐specific T‐cell activation. While long noncoding RNAs (lncRNAs) have emerged as critical regulators of immune cell fate and function, the lncRNA landscape governing human DC differentiation and effector activity remains incompletely defined. Here, we generated monocyte‐derived dendritic cells (moDCs) from primary human peripheral blood monocytes and performed transcriptome‐wide RNA sequencing to systematically identify previously unannotated lncRNAs associated with DC differentiation. We uncovered an extensive repertoire of novel lncRNA transcripts dynamically regulated during DC development. Among these, MSTRG.479558.1 and MSTRG.582898.5 were prioritized based on robust induction during differentiation, responsiveness to inflammatory stimulation (LPS), and elevated expression in periodontitis. Functional interrogation revealed a selective and non‐redundant role for MSTRG.479558.1 in DC biology. Knockdown of the lncRNA MSTRG.479558.1 but not MSTRG.582898.5 significantly reduced the expression of dendritic cell markers CD1a, CD209, and CDw93, indicating impaired dendritic cell differentiation. Functionally, MSTRG.479558.1 silencing profoundly impaired phagocytic capacity and antigen processing, indicating disruption at the earliest stages of antigen handling. Moreover, loss of MSTRG.479558.1 compromised antigen presentation and significantly attenuated DC‐mediated CD4 + T‐cell activation, and Th1 related cytokines IFNγ and TNF‐α, suggesting a functional link between this lncRNA and adaptive immune priming. Mechanistically, targeted transcriptional profiling demonstrated coordinated dysregulation of genes implicated in antigen processing and presentation pathways following MSTRG.479558.1 depletion, including components of proteasomal processing, chaperone‐mediated folding, and MHC‐associated peptide loading machinery. These findings support a model in which MSTRG.479558.1 acts as an upstream regulator of a transcriptional network that governs antigen handling and presentation. Collectively, this study defines a previously uncharacterized lncRNA program operative during human DC differentiation and identifies MSTRG.479558.1 as a critical regulator of DC functional competency. By coupling antigen acquisition to T‐cell activation, this lncRNA represents a novel layer of immune regulation with potential implications for inflammatory disease pathogenesis and therapeutic targeting.
ABSTRACT Liver fibrosis (LF) arises from chronic liver injury, in which a persistently pro‐inflammatory microenvironment shaped by hepatic macrophages drives hepatic stellate cells (HSCs) activation and fibrosis progression. The cyclic GMP‐AMP synthase (cGAS)–stimulator of interferon genes (STING) pathway serves as a molecular hub linking metabolic liver injury to immune and inflammatory responses, sensing danger signals from metabolic stress, mitochondrial injury, and cell death to initiate downstream inflammatory transcription. This signaling may sustain a pro‐inflammatory macrophage phenotype and amplify inflammation, potentially driving fibrosis from reversible repair toward progressive disease. This review summarizes the pathological mechanisms and translational advances of macrophage STING signaling in LF, discusses how STING integrates mitochondrial DNA (mtDNA) sensing with non‐canonical metabolic stress signals to sustain pro‐inflammatory macrophage states via bioenergetic and organelle remodeling, and evaluates emerging therapeutic strategies aimed at modulating macrophage STING signaling, including mesenchymal stem cell (MSC)/exosome‐based approaches and natural‐product interventions, for the potential therapeutic management of LF.
ABSTRACT Colorectal cancer (CRC) remains a global health concern and a leading cause of cancer mortality, where therapeutic resistance persists as the central barrier to sustained response. Most conventional therapies rely on apoptosis, but CRC frequently resists through p53 alterations, anti‐apoptotic BCL‐2 upregulation, and drug efflux mechanisms. Here, we explore unconventional cell death pathways, focusing on ferroptosis, as a strategy to overcome apoptosis‐dependent therapeutic resistance in CRC. We discussed the molecular mechanisms of ferroptosis, including GPX4 blockade, iron dysregulation, and lipid metabolism remodeling, and emphasized their implications for drug‐resistant CRC. Then, necroptosis, pyroptosis, and autophagy were discussed in relation to their crosstalk with ferroptosis. Preclinical models show that ferroptosis inducers (e.g., erastin, RSL3, talaroconvolutin) selectively kill chemoresistant CRC, including KRAS‐mutant CRC, and potentiate the efficacy of conventional regimens. The therapeutic duality of autophagy, pyroptosis, and necroptosis in CRC is discussed, with emphasis on ferroptosis's ability to circumvent traditional mechanisms of resistance. Yet, clinical translation is hindered by insufficient pharmacokinetics, systemic toxicity, limited biomarker availability, tumor heterogeneity, compensatory antioxidant pathways, and the need for safer delivery platforms. We propose that ferroptosis is most likely to enter CRC therapy through rational combinations, biomarker‐guided patient selection, and tumor‐targeted delivery platforms rather than as a stand‐alone cytotoxic strategy.
ABSTRACT Circadian rhythms orchestrate a host of biological processes in a time‐dependent manner to maintain homeostasis in response to exercise. Within this framework, Rev‐erb‐α, an intracellular nuclear receptor and transcriptional regulator, transcends its role in circadian rhythms to drive myogenesis, muscle remodeling, primary metabolism, and autophagy, underscoring its versatile, pleiotropic actions. This review consolidates experimental evidence from cell culture, genetically modified animal models, drug‐based approaches and humans, highlighting the role of Rev‐erb‐α mechanisms in skeletal muscle and exercise adaptation. Recent frontier‐of‐knowledge data indicate that acute and chronic exercise elicit distinct Rev‐erb‐α signatures. There is bimodal regulation: Rev‐erb‐α is downregulated immediately post‐exercise, followed by a subsequent increase, reflecting its primary role in pathway repression. In chronic conditions, the upregulation of Rev‐erb‐α can act as an adaptive mechanism that governs robust responses to energy demand and mitochondrial function, thereby coordinating the metabolic network, calcium homeostasis, and oxidative capacity. Also, Rev‐erb‐α overexpression or its pharmacological activation may reduce pathways associated with muscle atrophy, thereby preserving tissue function and muscle mass. Excitingly, higher physical activity levels increase the amplitude of Rev‐erb‐α over 24 h, enhancing health and performance. However, exercise timing determines the Rev‐erb‐α signature that affects downstream phenotypes in skeletal muscle. Thus, elucidating the mechanisms of regulation and action of the Rev‐erb‐α protein may offer new perspectives for improving or preserving muscle quality across different health conditions and diseases.
ABSTRACT Liver aging is characterized by structural remodeling and functional decline, frequently driven by mitochondrial dysfunction and senescence‐associated secretory phenotype (SASP). Sestrins (SESNs) are a family of stress‐inducible proteins, among which Sestrin1 and Sestrin2 are crucial for maintaining metabolic and redox homeostasis, yet their specific involvement in hepatic senescence remains unclear. In the present study, in vivo experiments were performed using WT mice at young, middle, and old ages, together with aged Sestrin1 −/− and Sestrin2 −/− mice. The aged mice displayed multifaceted hepatic dysfunction, accompanied by a progressive, age‐dependent decline of hepatic Sestrin1 and Sestrin2 expression. Intriguingly, hepatic cellular senescence, lipid deposition, oxidative stress and inflammation were significantly exacerbated in Sestrin1 ‐/‐ mice compared to Sestrin2 ‐/‐ and WT mice. To further explore the underlying mechanism, senescent AML12 cells overexpressing Sestrin1 were treated with or without mitochondrial division inhibitor‐1 (Mdivi‐1). Mechanistically, Sestrin1 preserved mitochondrial homeostasis by promoting mitochondrial fission via dynamin‐related protein 1 (Drp1), a master regulator of mitochondrial fission, and curtailing the leakage of mitochondrial DNA (mtDNA) into the cytoplasm, profoundly suppressing the cGAS‐STING pathway. However, these effects were abolished upon mitochondrial fission inhibition. Given that exercise training is a potent anti‐aging strategy known to upregulate SESNs protein levels, we further demonstrated that Sestrin1 is indispensable for its hepatoprotective benefits. Collectively, our results identified that the Sestrin1/Drp1/cGAS‐STING axis plays a pivotal role in liver aging and positioned Sestrin1 as a vital therapeutic target, serving as a key mediator of the anti‐aging benefits of exercise training.
